The Joint Center for Structural Genomics (JCSG-2) proposes to act as a production center for the Protein Structure Initiative (PSI-2). The JCSG has developed a high-throughput structural platform that will provide rapid structure determination by both x-ray crystallography and NMR on a range of targets from bacteria to human, and that will include challenging proteins, such as membrane proteins, eukaryotic proteins, and protein-protein complexes. Its goal is to constantly improve and update the pipeline through innovative technological advances, in order to both to increase the numbers of structures determined per year and reduce the cost per structure. A fundamental philosophy of JCSG-2 is to export those developments to the general structural biology community so that they can benefit from any novel methodologies and technologies. The JCSG will focus on protein families that are most likely to contain novel folds or whose folds cannot be predicted by current methodologies. The biological and biomedical focus will be on the "Central Machinery of Life" that constitutes those proteins conserved in the proteomes of all sequenced organisms. Subsets of these targets are likely to have important cellular roles implicated in disease. Furthermore, the JCSG-2 intends to leverage its HT platform to promote and extend the biological relevance of its structures, through collaborations with other NIH-funded consortia, such as the Center for Functional Glycomics, the Systems Approach to Innate Immunity-Inflammation-Sepsis, the Center on Proteolytic Pathways, the Cell Migration Consortium, the Alliance for Cell Signaling, as well as the recently formed KinaseNET. Similarly, technology advances in membrane and viral proteins will be jump started with the recent NIH-funding of the JCSG-affiliated "JCSG Center for Innovative Membrane Protein Technology" (JCIMPT), and the "Functional and Structural Proteomics Analysis of SARS-CoV Related Proteins." Other informal collaborations have been proposed with other PSI-2 technology development centers, on membrane proteins and protein complexes (PI Roger Kornberg, Stanford University), and protein complexes and eukaryotic proteins (PI Steve Almo, Albert Einstein College of Medicine). In summary, the overall JCSG-2 goal is to provide, at a reduced cost, a continuous flow of non-redundant, high-quality protein structures that, through judiciously chosen collaborations, will have a significant impact on the biological/biomedical sciences.